Cloned embryo can't fool a womb

The endometrium can differentiate between embryos generated by various technologies

Animal cloning could be a boon for the biotechnology and agricultural industries if only more livestock survived. Even though the percent of pregnancies initiated for cloned cow embryos is similar to that seen using other assisted fertilization techniques, only 7% of these embryos survive to be 150-day-old calves. The rest perish throughout pregnancy or soon after birth due to placental malformations. Two research groups have now demonstrated that the cow uterus reacts differently to embryos generated by cloning and by in vitro fertilization.

A group led by Eckhard Wolf at Ludwig-Maximilians University in Munich compared changes in endometrial gene expression induced by implantation of embryos obtained by either in vitro fertilization (IVF) or cloning (somatic cell nuclear transfer; SCNT), in which a nucleus is placed in an enucleated egg1. SCNT embryos elicited a more variable endometrial response than their IVF counterparts. Notably, even genetically identical embryos triggered different endometrial responses, which, according to the Wolf team, reflects a large amount of random variation created during the reprogramming of identical nuclei after they are transferred into eggs.

A companion study conducted by Olivier Sandra, Jean-Paul Renard and colleagues at the French National Institute for Agricultural Research in Paris reported similar observations. They compared endometrial response to embryos generated by IVF, SCNT and artificial insemination2. Their study shows subtle differences in the way that different areas of the uterine lining respond to each technology, providing additional evidence that the endometrium is sensitive to embryo manipulations that occur prior to implantation. Moreover, Sandra believes that this sensing property is not limited to cattle and suggests that their findings may be relevant for assisted reproduction in humans.

Still, neither study proves that the different expression profiles observed in the endometrium cause the low birthrates and frequent miscarriages typical of SCNT embryos. Showing causality would require taking endometrial biopsies without interrupting the pregnancy. That is technically very challenging with cattle, explains Wolf. "Nevertheless, we will try it", he says, adding that his team has successfully taken difficult biopsies before.

Both researchers agree that another interesting next step will be to identify the basis of the abnormal signaling of SCNT embryos to their maternal environment, which will require careful transcriptome and proteome analyses of both the embryos and the endometrium.

But Wolf says these studies also have a more immediate, practical message: deviations in the endometrial response can be used as a readout to optimize cloning procedures. Sandra agrees, and, fully aware of how demanding the effort to get there can be, he wonders if some day we will use endometrial responses as a prognosis (and not just a diagnosis) of pregnancy outcome.